Work from several laboratories (Nabel, et al., Science, 249:1285-1288 (1990); Lim, et al., Circulation, 83:2007-2011 (1991); Flugelman, et al., Circulation, 85:1110-1117 (1992); Leclerc, et al., J. Clin. Invest., 90:936-944 (1992); Chapman, et al., Circ. Res., 71: 27-33 (1992); Riessen, et al., Hum. Gene Ther., 4: 749-758 (1993); and Takeshita, et al., J. Clin. Invest., 93:652-661 (1994), has demonstrated that recombinant marker genes could be transferred to the vasculature of live animals.
Gene delivery systems employed to date have been characterized by two principal components: a macrodelivery device designed to deliver the DNA/carrier mixture to the appropriate segment of the vessel, and microdelivery vehicles, such as liposomes, utilized to promote transmembrane entry of DNA into the cells of the arterial wall. Macrodelivery has typically been achieved using one of two catheters initially developed for local drug delivery: a double-balloon catheter, intended to localize a serum-free arterial segment into which the carrier/DNA mixture can be injected, or a porous-balloon catheter, designed to inject gene solutions into the arterial wall under pressure. Jorgensen et al., Lancet 1:1106-1108, (1989); Wolinsky, et al., J. Am. Coil. Cardiol., 15:475-485 (1990); March et al., Cardio Intervention, 2:11-26 (1992)); WO93/00051 and WO93/00052.
Double balloon catheters are catheters which have balloons which, when inflated within an artery, leave a space between the balloons. The prior efforts have involved infusing DNA-containing material between the balloons, allowing the DNA material to sit for a period of time to allow transfer to the cells, and then deflating the balloons, allowing the remaining genetic material to flush down the artery. Perforated balloons are balloons which have small holes in them, typically formed by lasers. In use, fluid containing the genetic material is expelled through the holes in the balloons and into contact with the endothelial cells in the artery. These gene delivery systems however, have been compromised by issues relating to efficacy and/or safety.
Certain liabilities, however, inherent in the use of double-balloon and porous balloon catheters have been identified. For example, neither double-balloon nor porous balloon catheters can be used to perform the angioplasty itself. Thus, in those applications requiring both angioplasty and drug delivery, e.g., to inhibit restenosis, two procedures must be preformed. Additionally, the double balloon typically requires long incubation times of 20-30 min., while the high-velocity jets responsible for transmural drug delivery from the porous balloon catheter have been associated with arterial perforation and/or extensive inflammatory infiltration (Wolinsky, et al., J. Am. Coil. Cardiol., 15:475-481 (1990).